MicroRNA related genetic variation and head and neck cancer Head and neck squamous cell carcinoma (HNSCC) is a common and often disfiguring disease with a poor prognosis. Over 400,000 new cases of HNSCC are diagnosed annually worldwide, and most patients present with advanced disease. There is a recognized and incompletely described genetic susceptibility component in HNSCC genesis. Further, current prognostic models for HNSCC survival are based on staging and histopathologic criteria, are beginning to include HPV assessment, but lack robust genetic markers. This proposal will investigate the relationship between HNSCC risk and survival and a novel class of normal genetic variation, microRNA-related SNPs (miR-SNPs). MiR-SNPs include variation in miRNA target sites on mRNA transcripts, SNPs in miRNA genes, and SNPs in genes that participate in miRNA biogenesis and processing. While GWAS approaches have had some success, miR-SNPs have not been well represented on GWAS panels, and there is a very limited understanding of miRNA-related natural genetic variation. Almost exclusively non-coding, miR-SNPs clearly have critical regulatory capacity and the rapidly emerging literature has begun to demonstrate associations between candidate miR-SNPs and both risk and prognosis of human cancers including those of the head and neck. Recent and continued advances in miRNA target site prediction allows a more comprehensive cataloging and characterization of miR-SNPs that can be used for hypothesis testing in population studies. The primary aim of this work is to use proven epidemiologic resources to identify miR-SNPs associated with risk and prognosis of HNSCC, and to then validate identified associations in an independent population of HNSCC cases and controls. Previous work from our group has demonstrated a significant association between a SNP in the mature sequence of the miRNA gene MIR196A2 and risk of HNSCC, as well as the survival of patients with pharyngeal cancer. Separately, we observed a significant association between a let-7 miRNA target site in the 3'UTR of KRAS and survival of oral cancer patients. Further, in each of these reports on miR-SNPs and risk and survival of HNSCC we investigated the functional consequences of variant genotypes on expression of miRNAs and/or target gene transcripts. This proposal is a logical extension of our preliminary work and will extend well beyond candidate miR-SNP approaches by genotyping over 18,000 miR- SNPs. In our final aim, in conjunction with an extensive repertoire of molecular data from the parent study, we will use a systems genomics approach to explore the biological underpinnings and functional relevance of identified relationships between miR-SNPs and risk and prognosis of HNSCC. In addition, by integrating miR- SNP data with other molecular markers we will further refine identified markers of risk and prognosis to maximize their impact and translational potential.